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Background: Data are limited regarding the use of implantable cardioverter–defibrillators (ICDs) in diverse populations. This study explores cardiovascular (CV) outcomes and mortality from ICD randomized controlled trials (RCTs), by sex, race, and age. Methods: Five electronic databases (PubMed, Emcare, Embase, MEDLINE, and Cumulative Index to Nursing & Allied Health Literature CINAHL) were searched for dates from their inception to July 12, 2021, for RCTs of ICD therapy in adult patients. Data were analyzed for clinical outcomes, including all-cause or CV death, and heart failure hospitalization (HFH). Results: Among 5 RCTs (mean age: 63 years; 78% male; 76% White) with moderate overall risk of bias, clinical outcomes in patients with an ICD (n = 3260) vs a control group (n = 3685) were compared. No between-group sex differences were observed for all-cause death (odds ratio [OR] 0.86, P = 0.51), CV death (OR 0.98, P = 0.96), HFH (OR 0.95, P = 0.87), or HFH and all-cause death (OR 0.83, P = 0.51) in the ICD group, in a comparison of male vs female sex. All-cause death (OR 1.20, P = 0.67) did not differ for White vs Black patients receiving ICD therapy. Outcomes data for other non-White, non-Black race groups were often unreported. Most RCTs originated in North America, had male leadership, and were evenly sponsored by industry vs peer-reviewed funding. Conclusions: Outcomes data are sparse, by sex, race, and age, in current RCTs evaluating ICD therapy. Although ICD patient outcomes did not significantly differ by sex or race, improved data analyses and reporting are needed to determine the relationship between these sociocultural factors and clinical outcomes among distinct ICD patient cohorts. Résumé: Contexte: Les données sur l’utilisation des défibrillateurs cardioverteurs implantables (DCI) dans diverses populations sont limitées. Cette étude porte sur les résultats cardiovasculaires (CV) et les décès liés aux DCI qui ont été signalés dans le cadre d'essais contrôlés randomisés (ECR), en fonction du sexe, de la race et de l’âge. Méthodologie: Des recherches ont été effectuées dans cinq bases de données électroniques (PubMed, EmCare, Embase, Medline et CINAHL [Cumulative Index to Nursing & Allied Health Literature]) en ciblant une période allant de la date de leur création jusqu’au 12 juillet 2021 afin de recenser les ECR menés chez des patients adultes ayant reçu un DCI. Les données ont été analysées en fonction des résultats cliniques, notamment les décès toutes causes confondues ou d’origine CV et les hospitalisations pour insuffisance cardiaque (hIC). Résultats: Cinq ECR (âge moyen des patients : 63 ans; 78 % d’hommes; 76 % de race blanche) présentant globalement un risque de biais modéré ont permis de comparer les résultats cliniques obtenus chez les patients ayant reçu un DCI (n = 3 260) et ceux du groupe témoin (n = 3 685). Aucune différence intergroupe entre les sexes n’a été observée pour les décès toutes causes confondues (rapport de cotes [RC] : 0,86, p = 0,51), les décès d’origine CV (RC : 0,98, p = 0,96) et les hIC (RC : 0,95, p = 0,87), ou les hIC et les décès toutes causes confondues (RC : 0,83, p = 0,51) au sein du groupe de patients ayant reçu un DCI, dans une comparaison entre les sexes. Aucune différence entre les patients de race blanche et de race noire ayant reçu un DCI n’a été notée pour ce qui est des décès toutes causes confondues (RC : 1,20, p = 0,67). Souvent, les données sur les résultats obtenus au sein de groupes de patients de race autre que blanche ou noire n’étaient pas signalées. La plupart des ECR avaient été menés en Amérique du Nord, étaient dirigés par des hommes et commandités à parts égales par l’industrie et des organismes offrant du financement approuvé par les pairs. Conclusions: Les ECR portant sur l’utilisation des DCI fournissent actuellement peu de données sur les résultats en fonction du sexe, de la race et de l’âge. Les résultats obtenus chez les patients ayant reçu un DCI ne différaient pas significativement selon le sexe ou la race. Néanmoins, des analyses de données et des rapports plus détaillés sont nécessaires pour déterminer la relation entre ces facteurs socioculturels et les résultats cliniques au sein de cohortes distinctes de patients ayant reçu un DCI.

Tuberculosis (TB) is a chronic infectious granulomatous disease caused by the air-borne bacillus Mycobacterium tuberculosis and less frequently by other bacteria in the M. tuberculosis complex (Mycobacterium Bovis and Mycobacterium africanum). Tuberculous osteomyelitis of the condyle may present atypical clinical findings akin to temporomandibular joint arthritis or middle ear infections. A detailed clinical and radiographic examination aided by a histopathological and a microbiological diagnostic workup is the key to timely detection and administration of appropriate therapeutic regimens. A high degree of clinical suspicion is thus advocated in patients with such atypical presentations. We, hereby, are presenting a rare case of tuberculous osteomyelitis in a 15-year-old female child.

Background: Cardiac resynchronization therapy (CRT) is beneficial in patients who have heart failure with reduced ejection fraction or arrhythmic events. However, most randomized controlled trials (RCTs) showing survival benefits primarily enrolled older white men. This study aims to evaluate CRT efficacy by sex, race, and age in RCTs. Methods: Five electronic databases (CINAHL, Embase, Emcare, Medline, and PubMed) were searched from inception to July 12, 2021 for RCTs with CRT in adult patients. Data were analyzed for clinical outcomes including all-cause or cardiovascular (CV) death, worsening heart failure (HF), and HF hospitalization (HFH) according to sex, race, and age. Results: Among six RCTs with up to moderate risk of bias, 54% (n = 3,630 of 6,682; mean age 64 years, 22% female, 8% black patients) had CRT device implantation. All-cause death (odds ratio [OR], 0.51; P = 0.053) was reduced in female versus male CRT patients, whereas CV death, HFH, or all-cause death with worsening HF or HFH did not differ significantly. No difference was seen in CRT patients for all-cause death and worsening HF (OR, 1.32; P = 0.46) among white vs black patients or for all-cause death and HFH (OR, 1.19; P = 0.55) among ≥ 65 versus < 65 years. Conclusions: Whereas all-cause death was lower in female CRT patients, other reported outcomes did not significantly differ by sex, race, or age. Only 6 studies partially reported outcomes. Thus, enhanced reporting and analyses are required to overcome such paucity of data to evaluate the impact of these factors on clinical outcomes in distinct patient cohorts with CRT indication. RÉsumÉ: Contexte: La thérapie de resynchronisation cardiaque (TRC) est salutaire chez les patients qui souffrent d’insuffisance cardiaque avec fraction d’éjection réduite ou qui subissent des épisodes arythmiques. Toutefois, la plupart des essais contrôlés randomisés (ECR) montrant des bienfaits en matière de survie ont été principalement menés chez des hommes blancs âgés. Cette étude vise à évaluer l’efficacité de la TRC en fonction du sexe, de la race et de l’âge des participants aux ECR. Méthodologie: Nous avons effectué des recherches dans cinq bases de données électroniques (CINAHL, Embase, Emcare, Medline et PubMed) en ciblant une période allant de la date de leur création jusqu’au 12 juillet 2021 afin de recenser les ECR menés chez des patients adultes ayant subi une TRC. Les données ont fait l’objet d’une analyse axée sur les résultats cliniques, notamment les décès toutes causes confondues ou d’origine cardiovasculaire (CV), l’aggravation de l’insuffisance cardiaque (IC) et les hospitalisations pour cause d’IC (HIC), en fonction du sexe, de la race et de l’âge des patients. Résultats: Dans six ECR présentant un risque de biais tout au plus modéré, 54 % des patients (n = 3 630 sur 6 682; âge moyen : 64 ans, 22 % de femmes, 8 % de patients noirs) étaient porteurs d’un dispositif de RC. Les décès toutes causes confondues (rapport de cotes [RC] : 0,51; p = 0,053) étaient moins nombreux chez les femmes que chez les hommes parmi les patients ayant subi une TRC. En revanche, aucune différence significative entre les deux sexes n’a été relevée en ce qui concerne les décès d’origine CV, les HIC ou les décès toutes causes confondues liés à l’aggravation de l’IC ou aux HIC. Au sein de la population ayant subi une TRC, aucune différence n’a été observée quant aux décès toutes causes confondues et à l’aggravation de l’IC (RC : 1,32; p = 0,46) chez les patients blancs par rapport aux patients noirs. Il y avait aussi absence de différence quant aux décès toutes causes confondues et aux HIC (RC : 1,19; p = 0,55) chez les patients âgés de 65 ans ou plus par rapport aux patients âgés de moins de 65 ans au sein de la même population. Conclusions: Les décès toutes causes confondues étaient moins nombreux chez les femmes qui avaient subi une TRC, mais les autres résultats rapportés ne différaient pas significativement selon le sexe, la race ou l’âge des patients. Seulement six études ont signalé partiellement les résultats. Des rapports et des analyses plus détaillés sont nécessaires pour remédier à la paucité des données et ainsi permettre d’évaluer l’effet des facteurs étudiés sur les résultats cliniques au sein de cohortes distinctes de patients chez qui la TRC est indiquée.

Aims Associations between growth differentiation factor‐15 (GDF‐15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP‐1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. Methods and results FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF‐15 and change in GDF‐15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF‐15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF‐15 were more likely to be male and have more co‐morbidities. After adjustment, an increase in GDF‐15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF‐15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF‐15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF‐15 levels remained stable among participants randomized to liraglutide. Conclusions An increase in GDF‐15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF‐15 trajectory in informing risk of heart failure disease progression.

Objectives Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified d...

Aims Artificial intelligence (A.I) driven voice-based assistants may facilitate data capture in clinical care and trials; however, the feasibility and accuracy of using such devices in a healthcare environment are unknown. We explored the feasibility of using the Amazon Alexa (‘Alexa’) A.I. voice-assistant to screen for risk-factors or symptoms relating to SARS-CoV-2 exposure in quaternary care cardiovascular clinics. Methods We enrolled participants to be screened for signs and symptoms of SARS-CoV-2 exposure by a healthcare provider and then subsequently by the Alexa. Our primary outcome was interrater reliability of Alexa to healthcare provider screening using Cohen’s Kappa statistic. Participants rated the Alexa in a post-study survey (scale of 1 to 5 with 5 reflecting strongly agree). This study was approved by the McGill University Health Centre ethics board. Results We prospectively enrolled 215 participants. The mean age was 46 years (17.7 years standard deviation [SD]), 55% were female, and 31% were French speakers (others were English). In total, 645 screening questions were delivered by Alexa. The Alexa mis-identified one response. The simple and weighted Cohen’s kappa statistic between Alexa and healthcare provider screening was 0.989 (95% CI: 0.982, 0.997) and 0.992 (955 CI 0.985, 0.999) respectively. The participants gave an overall mean rating of 4.4 (out of 5, 0.9 SD). Conclusion Our study demonstrates the feasibility of an A.I. driven multilingual voice-based assistant to collect data in the context of SARS-CoV-2 exposure screening. Future studies integrating such devices in cardiovascular healthcare delivery and clinical trials are warranted. Registration https://clinicaltrials.gov/ct2/show/NCT04508972, Graphical Abstract Graphical Abstract

Women, older patients and non-White ethnic groups experience a substantial proportion of acute coronary syndromes (ACS), although they have been historically underrepresented in ACS randomized clinical trials (RCTs). To assess the influence of sex, age and race on major adverse cardiovascular events (MACE) and on heart failure events, we studied patients with type 2 diabetes in a large post-ACS trial (EXAMINE). Differences in baseline characteristics and the respective composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE) and cardiovascular death or heart failure hospitalization (HF events) were evaluated by subgroups in a cohort of post-ACS patients with diabetes, using unadjusted and adjusted Cox regression modelling. The EXAMINE trial enrolled 5380 patients with 35% aged > 65, 32% female and 27% non-White. The risk of MACE was higher in non-White compared to White patients after adjustment for potential confounding (HR = 1.35; 95% CI 1.04–1.75), but there were no significant differences by sex and age (HR = 1.03; 95% CI 0.87–1.22 for women; HR = 1.14; 95% CI 0.96–1.35 for patients ≥ 65 years). The risk of HF events was higher in non-White patients (HR = 1.56; 95% CI 1.13–2.14), and in patients aged > 65 (HR = 1.33; 95% CI 1.07–1.66) and nominally so in women (HR = 1.23; 95% CI 0.99–1.52). The additive risk of each demographic factor (women, older age and non-White race) was greater for HF events in comparison with MACE. Moreover, non-White elderly patients consistently had poorer prognosis regardless of sex. Older adults, women and non-White patients with diabetes who are post-ACS are often underrepresented in RCTs. The risk for HF events was higher in older and non-White patients, with a trend towards significance in women, whereas only non-White patients (and not women and older patients) were at higher risk for MACE. Future trials should enrich enrollment of these persons at risk.

Introduction While current guidelines currently recommend using warfarin, there is also a growing interest in the utilization of direct oral anticoagulants (DOACs) to treat left ventricular (LV) thrombus. Methods We performed a systematic search using PubMed, SCOPUS, EMBASE, Google Scholar, and ClinicalTrials.gov from inception to September 30th, 2020, for studies that had reported outcomes in patients with left ventricular thrombus treated with DOACs (PROSPERO registration number CRD42020219761) RESULTS: Twelve studies (n=867 patients) were included in the analysis. The pooled incidence of the systemic embolic events (SEE) with DOACs was 2.7%, while the thrombus resolution rate was 86.6%. The pooled incidence of overall bleeding (composite of major and minor bleeding) and major bleeding with DOACs were 5.6% and 1.1%, respectively. No significant difference was observed in terms of SEE (OR 0.81, 95% CI 0.44-1.52, p=0.54), major bleeding (OR 0.29, 95% CI 0.07-1.26, p=0.24), and failure of LV thrombus resolution (OR 0.86, 95% CI 0.28-2.58, p=0.68); while overall bleeding was significantly low in patients with LV thrombus treated with DOACs compared to vitamin K antagonists (VKAs) (OR 0.33, 95% CI 0.14-0.81, p=0.02) CONCLUSION: Our study demonstrates no significant difference in SEE, major bleeding, or failure of LV thrombus resolution between the two groups, thus demonstrating that DOACs are an efficacious and safe alternative for the treatment of LV thrombus compared to VKAs. However, further well-designed prospective trials are needed to answer important clinical questions - optimal dosing/duration of DOACs and its safety in the background of antiplatelet therapy. This article is protected by copyright. All rights reserved.

Background The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM ) risk stratifies patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk for heart failure (HF) hospitalization. The utility of TRS-HFDM in risk stratification for HF outcomes requires further validation. Materials and methods We used data from the control group of The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) trial (n=5123; mean follow up 4.8 years). The TRS-HFDM includes: prior HF (2 points), atrial fibrillation (1 point), coronary artery disease (1 point), estimated glomerular filtration rate 300 mg/g; 2 point and 30-300 mg/g; 1 point). We evaluated discrimination (Harrell C index) and calibration (Nam-D Agostino calibration statistic) of TRS-HFDM for time to HF hospitalization or death due to HF. Results The mean age of participants was 62.8±6.6 years, and 38% were female. The prevalence of TRS-HFDM for 0, 1, 2, 3 and 4+ were 42.1%, 34.9%, 14.6%, 6.0%, and 2.5% respectively. Increasing TRS-HFDM corresponded to an increasing HF risk: 1.3/1000 person years (PY) (TRS-HFDM : 0) to 64.7/1000 PY (TRS-HFDM : 4+). TRS-HFDM demonstrated robust discrimination for HF outcomes (C-index 0.78). Furthermore, the score was well calibrated for HF outcomes (calibration statistic p=0.13). Similar results were seen in participants without baseline HF (C-index 0.75). Conclusion The TRS-HFDM discriminates for HF specific risk among people with T2DM. Using the TRS-HFDM to identify those who maximally benefit from therapies that reduce HF risk warrants evaluation. This article is protected by copyright. All rights reserved.

Aims Among patients with acute myocardial infarction (AMI) complicated by heart failure [HF; clinical HF or left ventricular (LV) systolic dysfunction], we explored the probability of subsequent non-fatal cardiovascular (CV) events and sudden cardiac death (SCD). Methods and results The high-risk myocardial infarction (HRMI) database contains 28 771 patients with signs of HF or reduced LV ejection fraction ( Conclusion Among patients with AMI complicated by HF, SCD, compared with other causes of death, was less likely to be preceded by a non-fatal CV event. As patients are less likely to have preceding non-fatal CV events to alert the healthcare team of a possible impending SCD event, additional strategies for risk stratification for SCD are needed.

Background The EXAMINE trial tested the efficacy and safety of alogliptin, an inhibitor of dipeptidyl peptidase 4, compared with placebo in 5380 patients with type 2 diabetes and a recent acute coronary syndrome. Because alogliptin is cleared by the kidney, patients were stratified according to screening renal function within two independently randomized strata: (1) estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2 and (2) eGFR 2. We aim to assess the efficacy and safety of alogliptin vs. placebo according to the renal function strata. Methods Cox-proportional hazard models with an interaction term by renal function strata were used. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. Results Patient characteristics were balanced within each renal function strata. In total, 3946 patients were randomized within the eGFR ≥ 60 stratum, and 1434 patients within the eGFR p = 0.014. Cardiovascular death: eGFR ≥ 60 HR = 0.61, 95%CI, 0.42–0.88, and eGFR p = 0.013. Non-fatal MI: eGFR ≥ 60 HR = 0.86, 95%CI, 0.66–1.13, and eGFR p = 0.013. Conclusions Alogliptin may benefit patients with eGFR ≥ 60, but may be detrimental to patients with eGFR 2. These hypothesis-generating findings require further validation to assess the potential benefit and risk of alogliptin across the renal function spectrum among patients with type 2 diabetes and a recent acute coronary syndrome. Trial registration ClinicalTrials.gov, NCT00968708

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

Aims To develop a risk model for sudden cardiac death (SCD) in high‐risk acute myocardial infarction (AMI) survivors. Methods and results Data from the Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left Ventricular Dysfunction trial (CAPRICORN) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT) were used to create a SCD risk model (with non‐SCD as a competing risk) in 13 202 patients. The risk model was validated in the Eplerenone Post‐AMI Heart Failure Efficacy and Survival Study (EPHESUS). The rate of SCD was 3.3 (95% confidence interval 3.0–3.5) per 100 person‐years over a median follow‐up of 2.0 years. Independent predictors of SCD included age > 70 years; heart rate ≥ 70 bpm; smoking; Killip class III/IV; left ventricular ejection fraction ≤30%; atrial fibrillation; history of prior myocardial infarction, heart failure or diabetes; estimated glomerular filtration rate

OBJECTIVE Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD. RESEARCH DESIGN AND METHODS We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. RESULTS Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29–3.29]). Similar phenotypes and outcomes were identified in EXSCEL. CONCLUSIONS In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs.

Background There is uncertainty on how empagliflozin (EMPA) reduces blood pressure (BP), and in particular the potential role for changes in weight and haematocrit in mediating these effects. Purpose To assess the contributions of changes in weight and haematocrit on EMPA induced changes in BP in patients with type 2 diabetes mellitus (T2DM) in the EMPA-BP and EMPA-REG OUTCOME trials. Methods Patients received placebo (PBO), EMPA 10 mg or EMPA 25 mg. In EMPA-BP (12-week study), 823 patients with T2DM and hypertension (mean [SD] age 60.2 [9.0] years, HbA1c 7.90 [0.74] %, BMI 32.6 [5.1] kg/m2) were studied. In EMPA-REG OUTCOME, of the 7,020 treated patients with T2DM and cardiovascular disease (mean [SD] age 63.1 [8.6] years, HbA1c 8.07 [0.85] %, BMI 30.6 [5.3] kg/m2), 95.0% were on anti-hypertensive treatment at baseline. ANCOVA/MMRM models were applied to assess changes in systolic BP (SBP) at week 12 associated with, and independent of, changes in weight and haematocrit (Hct). SBP measurements are based on mean 24-h measurements from an ambulatory blood pressure monitoring (ABPM) device in EMPA-BP and seated office measurements in EMPA-REG OUTCOME. Results Mean (SD) baseline SBP was 131.7 (11.8), 131.3 (13.0) and 131.2 (12.1) mmHg in the PBO, EMPA 10 mg and EMPA 25 mg groups, respectively in EMPA-BP (mean 24-h SBP) and 135.8 (17.2), 134.9 (16.8) and 135.6 (17.0) mmHg (office SBP), respectively in EMPA-REG OUTCOME. In these relatively young patients with T2DM and mildly elevated mean SBP, EMPA reduced mean SBP by 3.4–4.2 mmHg compared with PBO (table) at week 12. Mean (SE) weight was reduced with EMPA (10 and 25mg) vs PBO treatment by −1.5 (0.2) kg and −2.0 (0.2) kg in EMPA-BP and by −1.2 (0.1) kg and −1.5 (0.1) kg in EMPA-REG OUTCOME at week 12. Mean (SE) haematocrit was increased by 2.1 (0.2) % and 1.8 (0.2) % versus placebo in EMPA-BP and by 2.2 (0.1) % and 2.5 (0.1) % in EMPA-REG OUTCOME with EMPA 10 mg and EMPA 25 mg, respectively. Weight loss accounted for 21–24% of the SBP reduction with EMPA treatment in EMPA-BP and 9–11% in EMPA-REG OUTCOME. Changes in Hct accounted for negligible (between −10% to 1%) SBP reduction with EMPA. Conclusion The reduction in SBP is modestly mediated through a reduction in weight. There was no meaningful effect of EMPA induced changes in Hct on SBP. Results were consistent using ABPM or office SBP. These findings suggest that EMPA's effects on SBP are likely mediated through other mechanisms such as natriuresis or reduction in arterial stiffness. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim and Eli Lilly and Company. Table 1

International audience; Aims: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit.Methods and results: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and machine learning algorithms. The mean age was 66 years and 30% of patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses [hazard ratio (95% confidence interval) comparing high- vs. low-dose losartan for the composite outcome of all-cause death or all-cause hospitalization: 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women; interaction P = 0.018]. Female sex clustered along with older age, ischaemic heart failure, New York Heart Association class III/IV, and estimated glomerular filtration rate

We investigated the effect of galectin-3 (Gal-3) inhibition with modified citrus pectin on markers of collagen metabolism in a proof-of-concept randomized placebo-controlled trial of participants with elevated Gal-3 levels and hypertension. Although higher Gal-3 levels were associated with female sex, diabetes, and reduced glomerular filtration rate in cross-sectional analyses, treatment with modified citrus pectin did not change collagen markers. The effect of Gal-3 inhibition among individuals with heart failure warrants further investigation.

IntroductionPatients with type 2 diabetes (T2D) have an increased risk of worsening kidney function (WKF) over time compared with patients without diabetes. Data evaluating the inter-relation between WKF, cardiovascular risk, and clinical events are scarce. We aim to study the association of WKF with subsequent cardiovascular events and the probabilities of transition from WKF to hospitalization or death according to patients’ risk. We have used a large population of patients with T2D and a high cardiovascular risk enrolled in the Action to Control Cardiovascular Risk in Diabetes Study.Research design and methodsTime-updated, joint, and multistate modeling were used. WKF was defined as an estimated glomerular filtration rate (eGFR) decline greater than 40% from baseline. A total of 10 251 patients were included, of whom 1213 (11.8%) presented WKF over a median (percentile25–75) follow-up time of 5.0 (4.1–5.7) years.ResultsPatients who experienced WKF were slightly older, more frequently women, and had longer diabetes duration. Patients experiencing WKF, regardless of baseline kidney function, had a higher risk of subsequent cardiovascular events, including the composite of cardiovascular death or hospitalization for heart failure (HHF), with ≈2-fold higher risk. Joint modeling showed that renal function deterioration frequently occurs even among patients who did not experience a cardiovascular event. In multistate models, patients with a medium-high cardiovascular risk (compared with those with a low cardiovascular risk) are at higher risk of HHF or cardiovascular death first (HR=4.76, 95% CI 3.63 to 6.23) than of WKF first (HR=1.37, 95% CI 1.21 to 1.56); remarkably, the risk of cardiovascular death or HHF is highest after a WKF event (HR=6.20, 95% CI 2.71 to 14.8).ConclusionsIn patients with T2D and a high cardiovascular risk, WKF occurs in more than 10% of patients and is independently associated with risk of subsequent cardiovascular events, irrespective of baseline eGFR. Preventing serious WKF and the transition from WKF to HHF or cardiovascular death is an important objective of future trials.Trial registration numberNCT00000620.

Purpose of review Antihyperglycemic therapies including sodium glucose contransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) have been demonstrated to confer significant cardiovascular benefit and reduce future events in patients with type 2 diabetes mellitus (T2DM). However, despite positive data from cardiovascular outcome trials, these therapies remain underutilized in a large proportion of patients who have clinical indications and meet coverage guidelines for their initiation. One of the causes of the observed gap between scientific evidence and clinical cardiology practice is therapeutic hesitancy (otherwise known as therapeutic inertia). The purpose of this review is to discuss the contributors to therapeutic hesitancy in the implementation of these evidence-based therapies and, more importantly, provide pragmatic solutions to address these barriers. Recent findings Recent studies have demonstrated that clinicians may not initiate cardiovascular protective therapies due to a reluctance to overstep perceived interdisciplinary boundaries, concerns about causing harm due to medication side effects, and a sense of unfamiliarity with the optimal choice of therapy amidst a rapidly evolving landscape of T2DM therapies. Summary Herein, we describe a multifaceted approach aimed at creating a 'permission to prescribe' culture, developing integrated multidisciplinary models of care, enhancing trainees' experiences in cardiovascular disease prevention, and utilizing technology to motivate change. Taken together, these interventions should increase the implementation of evidence-based therapies and improve the quality of life and cardiovascular outcomes of individuals with T2DM.

Background: We conducted a study to compare the duration of surgery in single dose intravenous antibiotic prophylaxis over no antibiotic prophylaxis in the prevention of wound infection following Lichtenstein tension free inguinal hernioplasty Methods: This prospective study was conducted in the Department of Surgery, Dr. Rajendra Prasad Government Medical College Kangra at Tanda from May 2018 to December 2019after being approved by institutional protocol review committe and ethics committee.50 patients were included in the study.These patients were randomised into two groups i.e. Group A (Antibiotic Group) and Group B (Non-antibiotic Group). Results: The mean duration of surgery in Antibiotic group (Group-A) was 56.6±15.66 minutes whereas it was 50.2±9.62 minutes in Non-antibiotic group (Group-B). The mean duration of surgery was more in Antibiotic group (Group-A) as compared to Non-antibiotic group (Group-B), however the difference was not statistically significant (p= 0.088). Conclusion: In our study, we concluded that statistically insignificant difference was found in the duration of surgery in Antibiotic and Non-antibiotic Group Keywords: Duration of surgery, Antibiotic, Pre-operative

Background: All the hernias, 75% occurs in groin and inguinal hernia is the most common form of all. Acquired hernia can be direct, indirect or combination of both. In adult males 65% of inguinal hernias are indirect and 55% of them are right side. Methods: This prospective study was conducted in the Department of Surgery, Dr. Rajendra Prasad Government Medical College Kangra at Tanda from May 2018 to December 2019after being approved by institutional protocol review committe and ethics committee.50 patients were included in the study. Results: In our study, the patients age ranged from 18 years to 87 years with a mean age of 50.26±15.76 years. 22 (44%) patients had inguinal hernia on right side Conclusion: We concluded that mostly patients were more than 50 yrs age group and right side. Keywords: Age, Site, Hernia

Purpose of Review With the rising cost of cardiovascular clinical trials, there is interest in determining whether new technologies can increase cost effectiveness. This review focuses on current and potential uses of voice-based technologies, including virtual assistants, in cardiovascular clinical trials. Recent Findings Numerous potential uses for voice-based technologies have begun to emerge within cardiovascular medicine. Voice biomarkers, subtle changes in speech parameters, have emerged as a potential tool to diagnose and monitor many cardiovascular conditions, including heart failure, coronary artery disease, and pulmonary hypertension. With the increasing use of virtual assistants, numerous pilot studies have examined whether these devices can supplement initiatives to promote transitional care, physical activity, smoking cessation, and medication adherence with promising initial results. Additionally, these devices have demonstrated the ability to streamline data collection by administering questionnaires accurately and reliably. With the use of these technologies, there are several challenges that must be addressed before wider implementation including respecting patient privacy, maintaining regulatory standards, acceptance by patients and healthcare providers, determining the validity of voice-based biomarkers and endpoints, and increased accessibility. Summary Voice technology represents a novel and promising tool for cardiovascular clinical trials; however, research is still required to understand how it can be best harnessed.

Author(s): Sharma, Abhinav; Wu, Jingjing; Ezekowitz, Justin A; Felker, Gary Michael; Udell, Jacob A; Heidenreich, Paul A; Fonarow, Gregg C; Mahaffey, Kenneth W; Hernandez, Adrian F; DeVore, Adam D | Abstract: AimsSodium-glucose co-transporter (SGLT)-2 inhibitors have been shown to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with type 2 diabetes mellitus (DM) and high cardiovascular risk in two large clinical outcome trials: empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS. The scope of eligibility for SGLT-2 inhibitors (empagliflozin and canagliflozin) among patients with type 2 DM and HF, based on clinical trial criteria and current US Food and Drug Administration (FDA) labelling criteria, remains unknown.Methods and resultsUsing data from the US Get With The Guidelines (GWTG)-Heart Failure registry, we evaluated the proportion of patients with DM and HF eligible for SGLT-2 inhibitor therapy based on the clinical trial criteria and the US FDA labelling criteria. The GWTG-HF registry is a quality improvement registry of patients admitted in hospital with HF in the USA. We included GWTG-HF registry participants meeting eligibility criteria hospitalized between August 2014 and 30 June 2017 from sites fully participating in the registry. The initial inclusion time point reflects when both drugs had FDA approval. Among the 139 317 patients (out of 407 317) with DM hospitalized with HF (in 460 hospitals; 2014 to 2017), the median age was 71 years, 47% (n = 65 685) were female, and 43% (n = 59 973) had HF with reduced ejection fraction. Overall, 43% (n = 59 943) were eligible for the EMPA-REG OUTCOME trial, 45% (n = 62 818) were eligible for the CANVAS trial, and 34% (n = 47 747) of patients were eligible for either SGLT-2 inhibitors based on the FDA labelling criteria. Among the FDA-eligible patients, 91.5% (n = 43 708) were eligible for either the EMPA-REG OUTCOME trial or the CANVAS trial. Patients who were FDA eligible, compared with those who were not, were younger (70.0 vs. 72.0 years of age), more likely to be male (57.7 vs. 50.3%), and had less burden of co-morbidities.ConclusionsThe majority of patients with DM who are hospitalized with HF are not eligible for SGLT-2 inhibitor therapies. Ongoing studies evaluating the safety and efficacy of SGLT-2 inhibitors among patients with HF may potentially broaden the population that may benefit from these therapies.

Summary: Background: Smartphone apps might enable interventions to increase physical activity, but few randomised trials testing this hypothesis have been done. The MyHeart Counts Cardiovascular Health Study is a longitudinal smartphone-based study with the aim of elucidating the determinants of cardiovascular health. We aimed to investigate the effect of four different physical activity coaching interventions on daily step count in a substudy of the MyHeart Counts Study. Methods: In this randomised, controlled crossover trial, we recruited adults (aged ≥18 years) in the USA with access to an iPhone smartphone (Apple, Cupertino, CA, USA; version 5S or newer) who had downloaded the MyHeart Counts app (version 2.0). After completion of a 1 week baseline period of interaction with the MyHeart Counts app, participants were randomly assigned to receive one of 24 permutations (four combinations of four 7 day interventions) in a crossover design using a random number generator built into the app. Interventions consisted of either daily prompts to complete 10 000 steps, hourly prompts to stand following 1 h of sitting, instructions to read the guidelines from the American Heart Association website, or e-coaching based upon the individual's personal activity patterns from the baseline week of data collection. Participants completed the trial in a free-living setting. Due to the nature of the interventions, participants could not be masked from the intervention. Investigators were not masked to intervention allocation. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in the modified intention-to-treat analysis set, which included all participants who had completed 7 days of baseline monitoring and at least 1 day of one of the four interventions. This trial is registered with ClinicalTrials.gov, NCT03090321. Findings: Between Dec 12, 2016, and June 6, 2018, 2783 participants consented to enrol in the coaching study, of whom 1075 completed 7 days of baseline monitoring and at least 1 day of one of the four interventions and thus were included in the modified intention-to-treat analysis set. 493 individuals completed the full set of assigned interventions. All four interventions significantly increased mean daily step count from baseline (mean daily step count 2914 [SE 74]): mean step count increased by 319 steps (75) for participants in the American Heart Association website prompt group (p

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

Purpose of review Although type 2 diabetes (T2D) is one of the most important risk factors that leads to the development of de novo heart failure, there are limited data, particularly from a practical/qualitative standpoint, about predictors of heart failure in this population. Recent findings Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to prevent the development of heart failure and the composite of heart failure and cardiovascular death in patients with T2D without known heart failure who have either established atherosclerotic vascular disease or multiple risk factors. The concept of primary prevention of heart failure has led many clinicians to inquire if there are specific risk/enrichment factors that may predict an increased risk of heart failure. Summary In this review, we identify some general and diabetes-specific risk factors that are associated with an increased risk of developing heart failure in people with T2D.

Cigarette smoking is one of the most important causes of illness and premature death. The tobacco problem in India is very complex, due to large use of an array of smoking forms well as smokeless tobacco products. Several recent publications have highlighted the requirement for the dental profession to get involved with tobacco intervention. Although approximately all of the toxicity of smoking is due to other harmful components present in cigarette smoke, the pharmacological effects of nicotine leads to tobacco addiction. Hence, all the attempts to quit smoking are aimed to remove tobacco addiction by replacing tobacco nicotine with clean nicotine. The most important cessation aid used, out of all the cessation aids, is nicotine replacement therapy or NRT. Nicotine replacement therapy (NRT) replaces much of the nicotine from tobacco, which is mixed with harmful chemicals, with clean nicotine, thus reducing motivation to consume tobacco and also lessening nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. NRTs show good results and have minimal adverse effects. The review aims to summarize literature on various modes of nicotine replacement therapy methods currently used and to discuss future possible approaches. Also, the safety and need of NRTs in various special conditions have been discussed. Keywords: Nicotine replacement therapy, Important cessation, Cigarette smoking.

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.

Background Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided. Methods This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity). Liver safety had been pre-identified as a concern, and within the phase 3 trials, was measured through (1) adverse event reporting, (2) central predefined liver monitoring schedule with various thresholds for potential drug-induced liver injury, and (3) blinded adjudication of serious liver toxicity by a panel of experts in drug-induced liver injury. A single data monitoring committee provided safety oversight across all trials within the program. Findings Prior to program termination, 7595 of 7602 (99.9%) randomized participants across the eight trials received at least one dose of the study drug (fasiglifam, placebo, or active control). No concerning trends were noted in adverse or serious adverse event frequency, suspected unexpected serious adverse reaction, alanine or aspartate transaminase elevations, or hepatobiliary or gastrointestinal adverse events as reported by local site investigators. However, the predefined central liver safety measurements revealed a greater frequency of possible Hy’s Law cases (5 vs 2) and a 3- to 7-fold greater relative risk in alanine or aspartate transaminase elevation (with respect to upper limit of normal) within fasiglifam recipients compared with placebo/active control: alanine or aspartate transaminase > 3×: relative risk 3.34 (95% confidence interval 2.29–4.90), alanine or aspartate transaminase > 5×: relative risk 6.60 (95% confidence interval 3.03–14.38), alanine or aspartate transaminase > 8×: relative risk 6.14 (95% confidence interval 2.18–17.27), and alanine or aspartate transaminase > 10×: relative risk 6.74 (95% confidence interval 2.05, 22.14). All elevations resolved on study drug discontinuation. Drug-induced liver injury was adjudicated as highly likely or probably related in 0.64% of fasiglifam-treated versus 0.06% placebo or active control-treated patients. Conclusion In spite of clear liver toxicity detected with a systematic surveillance program, liver safety signals were not identified from investigator adverse event reporting alone. By integrating key safety monitoring processes within the randomized design of adequately sized clinical trials, the rare but serious liver toxicity signal became clear, leading to timely program termination.

Background: Minor salivary gland benign tumors account for a very small percentage of salivary gland tumors of which monomorphic adenomas are a rare entity. Methods and Findings: The present case report discusses a rare case report of an 18-year-old female patient diagnosed with monomorphic adenoma of the posterior palatal region. The diagnosis was reached after thorough radiographical and pathological investigations. Conclusion: Monomorphic Adenoma in a younger individual is a rare disorder and can be used as a collective term for benign or malignant tumors comprising of one type or even two types of cells.

Background Actigraphy-based measurements of physiologic parameters may enable design of patient-centric heart failure (HF) clinical trials. Recently, the Heart Failure Collaboratory (HFC) focused on recommendations for meaningful change and use of actigraphy as an endpoint in HF clinical trials. We aimed to evaluate randomized controlled trials (RCTs) that have quantified the impact of HF interventions using actigraphy. Methods Using a scoping review strategy, we evaluated the use of actigraphy in HF RCTs. Studies were identified through electronic searches of Embase, OVID MEDLINE, PubMed, and Cochrane review. Data on trial characteristics and results were collected. Results We identified 11 RCTs with a total of 1,455 participants. The risk of bias across the included trials was overall high. All trials had the primary outcomes reflecting measures of either physical activity (n=8), sleep (n=2), or both (n=1). Five trials evaluated response to pharmacologic therapies compared to placebo, three evaluated physical activity interventions, two evaluated group or cognitive therapy, and one evaluated sleep-ventilation strategy. Sample sizes ranged from 30 to 619 participants. There was significant heterogeneity relating to device type, body placement site, and handling of missing actigraphy data. Duration of monitoring ranged from 48 hours to 12 weeks. None of the studies evaluating pharmacologic therapies (n=5) demonstrated a significant improvement of actigraphy-based primary endpoints measurements. Conclusions There is significant heterogeneity in the use, methodology, and results of actigraphy-based HF RCTs. Our results highlight the need to develop, standardize, and validate actigraphy-specific outcomes for use in HF clinical trials

Objectives The aim of the RAAS-COVID-19 randomized control trial is to evaluate whether an upfront strategy of temporary discontinuation of renin angiotensin aldosterone system (RAAS) inhibition versus continuation of RAAS inhibition among patients admitted with established COVID-19 infection has an impact on short term clinical and biomarker outcomes. We hypothesize that continuation of RAAS inhibition will be superior to temporary discontinuation with regards to the primary endpoint of a global rank sum score. The global rank sum score has been successfully used in previous cardiovascular clinical trials. Trial design This is an open label parallel two arm (1,1 ratio) randomized control superiority trial of approximately 40 COVID-19 patients who are on chronic RAAS inhibitor therapy. Participants Adults who are admitted to hospital within the McGill University Health Centre systems (MUHC) including Royal Victoria Hospital (RVH), Montreal General Hospital (MGH) and Jewish General Hospital (JGH) and who are within 96 hours of COVID-19 diagnosis (confirmed via PCR on any biological sample) will be considered for the trial. Of note, the initial protocol to screen and enrol within 48 hours of COVID-19 diagnosis was extended through an amendment, to 96 hours to increase feasibility. Participants have to be 18 years or older and would have to be on RAAS inhibitors for at least a month to be considered eligible for the study. Additionally, RAAS inhibitors should not have been held for more than 48 hours before randomization. A list of inclusion and exclusion criteria can be found in the full protocol document. In order to prevent heart failure exacerbation, patients with reduced ejection fraction were excluded from the trial. Once a patient is admitted on the ward with a diagnosis of COVID-19, we will confirm with the treating physician if the participant is suitable for the RAAS-COVID trial and meets all the inclusion and exclusion criteria. If the patient is eligible and informed consent has been obtained we will collect data on sex, age, ethnicity, past medical history and list of medications (e.g. other anti-hypertensives or anticoagulants), for further analysis. Intervention and comparator All the study participants will be randomized to a strategy of temporarily holding the RAAS inhibitor [intervention] versus continuing the RAAS inhibitor [continued standard of care]. Among participants who are randomized to the intervention arm, alternative guide-line directed anti-hypertensive medication will be provided to the treating physician team (detail in study protocol). In the intervention arm RAAS inhibitor will be withheld for a total of 7 days with the possibility of the withdrawn medication being initiated at any point after day 7 or on the day of discharge. The recommendation for re-initiating the withdrawn medication will be made to the treating physician. The re-initiation of these therapies are according to standard convention and follow-up as per Canadian guidelines. Additionally, the date of restarting the withdrawn medication or whether the medication was re-prescribed on discharge or not, will be collected. This will be used to conduct a sensitivity analysis. Furthermore, biomarkers such as troponin, c-reactive protein (CRP) and lymphocyte count will be assessed during the same time period. Samples will be collected on randomization, day 4 and day 7. Main outcomes Primary endpoint In this study the primary end point is a global rank score calculated for all participants, regardless of treatment assignment ( score from 0 to 7). Please refer to table 4 in the full protocol. In the context of the current trial, it is estimated that death is the most meaningful endpoint, and therefore has the highest score ( score of 7). This is followed by admission to ICU, the need for mechanical ventilation etc. The lowest scores ( score of 1) are assigned to biomarker changes (e.g. change in troponin, change in CRP). This strategy has been used successfully in cardiovascular disease trials and therefore is applicable to the current trial. The primary endpoint for the present trial is assessed from baseline to day 7 (or discharge). Participants are ranked across the clinical and biomarker domains. Lower values indicate better health (or stability). Participants who died during the 7th day of the study will be ranked based on all events occurring before their death and also including the fatal event in the score. Next, participants who did not die but were transferred to ICU for invasive ventilation will be ranked based on all the events occurring before the ICU entry and also including the ICU admission in the score. Those participants who did not die were not transferred to ICU for invasive ventilation, will be ranked based on the subsequent outcomes. The mean rank score will then be compared between groups. In this scheme, a lower mean rank score indicates greater overall stability for participants. Secondary endpoints : The key secondary endpoints are the individual components of the primary components and include the following: death, transfer to ICU primarily for invasive ventilation, transfer to ICU for other indication, non-fatal MACE ( any of following, MI, stroke, acute HF, new onset Afib), length of stay > 4 days, development of acute kidney injury ( > 40% decline in eGFR or doubling of serum creatinine), urgent intravenous treatment for high blood pressure, 30% increase in baseline high sensitivity troponin, 30% increase in baseline BNP, increase in CRP to > 30% in 48 hours and lymphocyte count drop> 30%. We will also look at the World Health Organization (WHO) ordinal scale for clinical improvement (in COVID-19) in our data. In this scale death will be assigned the highest score of 8. Patients with no limitation of activity will be assigned a score of 1 which indicates overall more stability (3). Additionally, we will evaluate the potential effects of discontinuing RAAS inhibition on alternative schedules (longer/shorter than 7 days, intermittent discontinuation) using a mechanistic mathematical model of COVID-19 immunopathology calibrated to data collected from our patient cohort. In particular, we will assess the impact of alternative schedules on primary and secondary endpoints including increases to baseline CRP and lymphocyte counts. Randomization Participants will be randomized in a 1:1 ratio. Randomization will be performed within an electronic database system at the time of enrolment using a random number generator, an approach that has been successfully used in other clinical trials. Neither participant, study team, or treating team will be blinded to the intervention arm. Blinding This is an open label study with no blinding. Numbers to be randomised (sample size) The approximate number of participants required for this trial is 40 patients (randomized 1:1 to continuation versus discontinuation of RAAS inhibitors). This number was calculated based on previous rates of outcomes for COVID-19 in the literature (e.g. death, ICU transfer) and statistical power calculations. Trial Status Protocol number: MP-37-2021-6641, Version 4: 01-10-2020. Trial start date September 1st 2020 and currently enrolling participants. Estimated end date for recruitment of participants : July 2021. Estimated end date for study completion: September 1st 2021. Trial registration Trial registration: ClincalTrials.gov: NCT04508985, date of registration: August 11th , 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

International audience; In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.

Background Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24-hour ultrafiltration-based fluid removal above versus below the median. Patients were stratified by EF (40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy. Dr. Fudim is supported by an American Heart Association Grant, 17MCPRP33460225; he consults for Coridea, AxonTherapies, Galvani, and Daxor. Dr. Greene has received research support from a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis, Amgen, Bristol-Myers Squibb and Novartis; and serves on an advisory board for Amgen. Dr. Sharma has received research support from the Fonds de la recherche en sante du Quebec (FRSQ)-Junior 1, Jean Roy award in Cardiology (McGill University), Akcea, Pharma, Solutions, Alberta Innovates Health Solutions, Bayer-Canadian Cardiovascular Society, Boehringer-Ingelheim, Roche Diagnostics, and Takeda. Dr. Verbrugge was supported by a Fellowship of the Belgian American Educational Foundation. Dr. Martens has received consultancy fees from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Novartis, and Vifor Pharma and an unrestricted research grant from Vifor Pharma. Dr. Grodin receives research support from the Texas Health Resources Clinical Scholars fund and has received consultancy fees from Pfizer, Inc. Dr. Hernandez receives Grant/Research Support; Company Relationship; AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Luitpold Pharmaceuticals, Merck, Novartis. Honoraria; Company Relationship; Bayer, Boston Scientific, Novartis. Dr. Felker has received research funding from Otsuka, Novartis, Roche Diagnostics, Amgen, Merck, American Heart Association, and the National Heart, Lung, and Blood Institute; and has served as a consultant for Novartis, Roche Diagnostics, Amgen, Trevena, Cytokinetics, Madeliene, Myokardia, Bristol-Myers Squibb, Stealth Biotherapeutics, and GlaxoSmithKline. Dr. Mentz receives research support from the National Institutes of Health (U01HL125511-01A1, U10HL110312, and R01AG045551-01A1), Akros, Amgen, AstraZeneca, Bayer, GlaxoSmithKline, Gilead, Luitpold, Medtronic, Merck, Novartis, Otsuka, and ResMed; honoraria from Abbott, AstraZeneca, Bayer, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, and ResMed; and has served on an advisory board for Amgen, Luitpold, Merck, and Boehringer Ingelheim. The remaining authors have no disclosures to report. Fudim, M (corresponding author), 2301 Erwin Rd, Durham, NC 27713 USA. marat.fudim@gmail.com

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-19) has emerged as a public health emergency in recent times. The reported data on the mode of transmission of coronavirus disease 2019 (COVID-19) are largely through contact, droplet, airborne and fomite transmission methods with vertical transmission being a rare entity. We hereby report a case of a probable vertical transmission of SARS-CoV-19 from an infected pregnant female to her neonate. The transmission has been confirmed by a positive RT-PCR at 16 h of life along with a positive IgG antibody test for SARS-CoV-19 in the baby and after excluding the possible environmental contamination of the sample. The baby was asymptomatic during the course of hospital stay and was discharged from the facility on Day 9 of life.

Background: The effect of menopausal status on the risk factors of cardiovascular (CV) disease is not well ascertained. We aimed to evaluate the impact of menopause on several traditional and non-traditional cardiovascular (CV) risk factors. Methods: The CARTaGENE study was a prospective cohort study with random sampling of individuals in Quebec, Canada. We completed a seven-year follow-up in 2016. For this analysis, we included only subjects without prior cardiovascular (CV) events (CVE) or CV interventions (CVI). We defined the primary endpoint as CVE which can be any of the following events: acute coronary syndromes, heart failure, strokes, CV deaths, and peripheral vascular events. The secondary endpoint was CVI which included coronary, carotid, or peripheral artery revascularization. We used Cox proportional hazard stepwise multivariate analyses to identify independent predictors of the primary endpoint separately in pre- and post-menopausal women. Results Of 9,529 women without prior CV disease, 57% were post-menopausal. The mean age was 47.4 years and 58.6 years for pre-menopausal and post-menopausal women, respectively. There were 793 CVEs and 83 CVIs with a median time to event of 6.6 years. Hypertension, active smoking, increased waist to hip ratio, and glycosylated hemoglobin were independent predictors of the primary endpoint in both pre- and post-menopausal women. Furthermore, advanced age, family history of myocardial infarction, prior cancer, increased gamma-glutamyl transferase, and hyperuricemia also predicted increased riks of the primary endpoint in post-menopausal women. Conclusion: Hypertension, active smoking, increased waist to hip ratio, and high glycosylated hemoglobin were associated with increased CV risk in pre-menopausal women. The impact of hypertension was markedly amplified in pre-menopausal women compared to postmenopausal women. Intensive blood pressure control should be considered in pre-menopausal women.

Background: Patients with type 2 diabetes mellitus (T2DM) are at an increased risk for developing heart failure (HF), and clinical models are needed to identify patients with a greater risk for HF hospitalization (HHF). The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM) was recently developed and validated to predict HHF in patients with T2DM in two large clinical trials (SAVOR-TIMI 53 and DECLARE-TIMI 58). We aimed to validate the TRS-HFDM in another cohort of patients with T2DM. Methods: We validated the TRS-HFDM score in 5,123 patients with T2DM for fatal or non-fatal HHF in the placebo arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes Study Group). The TRS-HFDM included: prior HF, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. We evaluated discrimination with the Harrell C index, and calibration by comparing observed event rates for HHF with predicted risk, and the Nam-D’Agostino statistic. Results: During a mean follow up of 4.8 years, 212 patients (4.14%) experienced at least one HHF. The mean age was 63 ±6.7 years, and 38% were female. The baseline hemoglobin A1C was 8.3%, and 36% were on insulin. The ACCORD patients had less comorbidities with a lower proportion of patients with renal dysfunction (8% vs. 16% vs. 17%), established cardiovascular disease (35% vs.79% vs. 41%) and pre-existing HF (5% vs. 13% vs. 10%) compared to patients enrolled in the SAVOR-TIMI 53 and DECLARE TIMI-58 trials respectively. In our cohort, the TRS-HFDM score predicted well HHF events with a Harrel C index of 0.78. The integer-based score was well calibrated, with the observed Kaplan-Meier HHF rates closely predicting the Kaplan-Meier event rates at the end follow up (Nam D`Agostino test: 65.39 (p Discussion: Our findings confirm the applicability of the TRS-HFDM in a large cohort of patients with T2DM with less high-risk features than the SAVOR-TIMI 53 and DECLARE-TIMI 58 populations. Future validation of this risk score in observational cohort studies is needed to evaluate its external validity in a general clinical setting.

Background The timing of enrolment following an acute coronary syndrome (ACS) may influence cardiovascular (CV) outcomes and potentially treatment effect in clinical trials. Using a large contemporary trial in patients with type 2 diabetes mellitus (T2DM) post-ACS, we examined the impact of timing of enrolment on subsequent CV outcomes. Methods EXAMINE was a randomized trial of alogliptin versus placebo in 5380 patients with T2DM and a recent ACS. The primary outcome was a composite of CV death, non-fatal myocardial infarction [MI], or non-fatal stroke. The median follow-up was 18 months. In this post hoc analysis, we examined the occurrence of subsequent CV events by timing of enrollment divided by tertiles of time from ACS to randomization: 8–34, 35–56, and 57–141 days. Results Patients randomized early (compared to the latest times) had less comorbidities at baseline including a history of heart failure (HF; 24.7% vs. 33.0%), prior coronary artery bypass graft (9.6% vs. 15.9%), or atrial fibrillation (5.9% vs. 9.4%). Despite the reduced comorbidity burden, the risk of the primary outcome was highest in patients randomized early compared to the latest time (adjusted hazard ratio [aHR] 1.47; 95% CI 1.21–1.74) (Figure 1). Similarly, patients randomized early had an increased risk of recurrent MI (aHR 1.51; 95% CI 1.17–1.96) and HF hospitalization (1.49; 95% CI 1.05–2.10). Conclusion In a contemporary cohort of T2DM with a recent ACS, early randomization following the ACS increases the risk of CV events including recurrent MI and HF hospitalization. This should be taken into account when designing future clinical trials. Figure 1 Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Takeda Pharmaceutical

Background Sudden cardiac death (SCD) is responsible for 20–40% of mortality following acute myocardial infarction (AMI). The risk of SCD is even higher among patients with AMI complicated by heart failure (HF) (either clinically apparent HF or left ventricular dysfunction). The temporal relationship between an AMI complicated by HF and subsequent SCD and the association of non-fatal cardiovascular (CV) events following AMI with SCD has yet to be described. Purpose Among patients with AMI complicated by HF, we evaluated the probability and temporal association of subsequent non-fatal cardiovascular (CV) events (HF hospitalization, recurrent MI, or stroke) and SCD. Methods The High-Risk Myocardial Infarction (HRMI) database contains 28,771 patients with signs of HF or reduced LV ejection fraction ( Results Median follow-up was 1.9 years. Mean age was 65.0±11.5 years and 70% were male. The incidence of CV death was 7.9 per 100 patient-year [py] and for SCD was 3.1 per 100py (40% of CV deaths). SCD rates were highest in the early period ( Conclusion Among patients with AMI complicated by HF, SCD predominantly occurred in the early “high-risk” period after AMI; SCD rates decreased afterwards. Patients with non-fatal HF hospitalizations during follow-up may have a higher subsequent SCD risk. Preventing HF onset after MI may help decreasing SCD. Proportion of sudden cardiac death Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Lucien Award, McGill University

Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. Methods and results This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS‐HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter‐quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P

International audience; Background: Patients with diabetes who had a recent myocardial infarction (MI) are at high risk of cardiovascular events. Therefore, risk assessment is important for treatment and shared decisions. We used data from EXAMINE trial to investigate whether a multi-proteomic approach would provide specific proteomic signatures and also improve the prognostic capacity for determining the risk of cardiovascular death, MI, stroke, heart failure [HF], all-cause death, and combinations of these outcomes.Methods: 93 circulating proteins (92 from the Olink® CVDII plus troponin) were assessed in 5131 patients. Cox, competing risks, and reclassification measures were applied.Results: The clinical model showed good discrimination and calibration for all outcomes. On top of the clinical model that included age, sex, smoking, diabetes duration, history of MI (prior to the index MI of inclusion), history of HF hospitalization, history of stroke, atrial fibrillation, hypertension, systolic blood pressure, statin therapy, estimated glomerular filtration rate, and study treatment (alogliptin or placebo), troponin and BNP added prognostic information to the composite of cardiovascular death, MI, or stroke (∆C-index + 5%) and cardiovascular death alone (∆C-index + 7%). Troponin, BNP, and TRAILR2 added prognostic information on all-cause death and the composite of cardiovascular death or HF hospitalization. HF hospitalization alone was improved by adding BNP and Gal-9. For MI, troponin, FGF23, and AMBP added prognostic value; whereas for stroke, only troponin added prognostic value (multi-proteomics improved C-index > 3% [p < 0.001] for all the studied outcomes). The addition of the final biomarker selection to the clinical model improved event reclassification (cNRI from + 23% to + 64%). Specifically, the addition of the biomarkers allowed a better classification of patients at low risk (as having "true" low risk) and patients and high risk (as having "true" high risk). These results were consistent for all the studied outcomes with even more marked differences in the fatal events.Conclusions: The addition of multi-proteomic biomarkers to a clinical model in this population with diabetes and a recent MI allowed a better risk prediction and event reclassification, potentially helping for better risk assessment and targeted treatment decisions. T2D type 2 diabetes, MI myocardial infarction, CV cardiovascular, HFH heart failure hospitalization, Δ delta, cNRI continuous net reclassification index, BNP brain natriuretic peptide, TRAILR2 trail receptor 2 (or death receptor 5), Gal-9 galectin-9, FGF23 fibroblast growth factor 23

Background There are conflicting data regarding the benefit of primary prevention implantable cardioverter‐defibrillators ( ICD s) in patients with diabetes mellitus and heart failure (HF) with reduced ejection fraction. We aimed to assess the comparative effectiveness of ICD placement in patients with diabetes mellitus and HF with reduced ejection fraction. Methods and Results Data were obtained from the Get With the Guidelines–Health Failure registry, linked with claims from the Centers for Medicare & Medicaid Services. We used a Cox proportional hazards model censored at 5 years with propensity score matching. Of the 17 186 patients with HF with reduced ejection fraction from the Centers for Medicare & Medicaid Services claims database (6540 with diabetes mellitus; 38%), 1677 (646 with diabetes mellitus; 39%) received an ICD during their index HF hospitalization or were prescribed an ICD at discharge. Patients with diabetes mellitus and an ICD (n=646), as compared with those without an ICD (n=1031), were more likely to be younger (74 versus 78 years of age) and have coronary artery disease (68% versus 60%). After propensity matching, ICD use among patients with diabetes mellitus, as compared with those without an ICD , was associated with a reduced risk of all‐cause mortality at 5 years after HF discharge (54% versus 59%; multivariable hazard ratio, 0.73; 95% CI , 0.64–0.82; P ICD use and all‐cause mortality ( P =0.95 for interaction). Similar results were seen in patients without diabetes mellitus. Conclusions Primary prevention ICD use among older patients with HF with reduced ejection fraction and diabetes mellitus was associated with a reduced risk of all‐cause mortality. Our analysis supports current guideline recommendations for implantation of primary prevention ICD s among older patients with diabetes mellitus and HF with reduced ejection fraction.